IL-33 signaling as a target to reduce ventilator-induced lung inflammation

IL-33 信号传导作为减少呼吸机引起的肺部炎症的靶点

• 批准号: 10704302
• 负责人: Guido Musch
• 金额: $ 81.02万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704302
• 关键词: Acute Respiratory Distress Syndrome; Address; Affinity; Allergic inflammation; Binding; Biological; Biological Markers; Biological Response Modifier Therapy; Blocking Antibodies; Cell membrane; Cells; Clinical; Critical Illness; Data; Epidemic; Epithelial; Gene Expression; General Anesthesia; Genetic Transcription; Goals; Hour; Immune; Inflammation; Inflammation Mediators; Inflammatory; Injury; Intensive Care Units; Interleukin-1 Receptors; Interleukin-13; Interleukin-4; Interleukin-5; Interleukin-6; Interruption; Intubation; Knockout Mice; Knowledge; Lead; Light; Link; Lung; MAP Kinase Gene; Measures; Mechanical ventilation; Mechanics; Mediating; Mediator of activation protein; Methods; Modeling; Morbidity - disease rate; Mus; Operating Rooms; Operative Surgical Procedures; Organ; Pathogenesis; Pathway interactions; Patients; Pilot Projects; Poliomyelitis; Positron-Emission Tomography; Postoperative Period; Process; Production; Proteins; Pulmonary Inflammation; Rattus; Recombinants; Reporter; Reporting; Research; Resolution; Role; Signal Pathway; Signal Transduction; Testing; Th2 Cells; Therapeutic; Therapeutic Intervention; Tidal Volume; Time; Transgenic Organisms; Treatment Efficacy; Ventilator; Ventilator-induced lung injury; clinical practice; clinically relevant; cytokine; effective therapy; experimental study; imaging modality; immunogenicity; improved; in vivo; interest; mechanical pressure; mechanical stimulus; molecular imaging; mortality; mouse model; non-invasive imaging; novel; preventive intervention; public health relevance; receptor; response; stem; therapeutic target; uptake; ventilation

PROJECT SUMMARY/ABSTRACT Since being heralded into clinical practice by the Danish polio epidemic of 1952, positive pressure mechanical ventilation has saved countless lives and enabled the safe practice of surgery under general anesthesia. In recent years, however, it has become clear that mechanical ventilation itself can injure the lung by initiating and propagating an inflammatory process termed ventilator-induced lung injury (VILI). Whereas VILI was initially mainly considered an aggravating factor for critically ill patients with acute respiratory distress syndrome, new evidence suggests that it can occur also in subjects with uninjured lungs undergoing ventilation for other reasons, for example while receiving general anesthesia. The long-term goal of this research is to dissect the mechanisms of VILI and identify strategies to ameliorate it. The proposed studies align with this goal because they investigate a novel role for the IL-33/ST2 signaling pathway by addressing the overarching hypothesis that IL-33 is an upstream pathogenetic effector of VILI through its effect on NF-κB mediated inflammation. This hypothesis will be tested through three closely knit specific aims. Aim 1 will establish the role of IL-33 in VILI by demonstrating that its expression increases with tidal volume, that it parallels the response of established VILI cytokines and NF-κB, and that IL-33 deletion blunts such response. Aim 2 builds on aim 1 by probing the efficacy of IL-33 scavenging with IL-33 decoy receptors as an approach for interrupting IL-33/ST2/NF-κB signaling and decreasing inflammation in VILI. This aim will leverage a novel biologic with high affinity for IL-33 (“IL-33 trap”) that preliminary data suggest could have therapeutic potential. The IL-33 trap will be compared with the more traditional approach of anti-ST2 receptor blocking antibodies. Aim 3 flows from aims 1 and 2 as it will determine for how long the activation of NF-κB triggered by release of mechano- sensitive cytokines like IL-33 persists after ventilation ceases, thus rendering the lung vulnerable to other insults, as are those that can occur in the postoperative period. A distinctive feature that permeates all three aims of this project is the application of a unique molecular imaging method based on positron emission tomography (PET) of NF-κB transcriptional activity to measure the effect of IL-33/ST2 signaling on downstream cytokine expression in vivo, noninvasively, repeatedly and with high spatial resolution. It is expected that the combination of clinically relevant murine ventilation model, novel VILI effector (IL-33, aim 1), therapeutic biologic (IL-33 trap, aim 2), and translational perspective (aim 3), will make the proposed experiments uniquely poised to yield fundamental new knowledge on the pathogenesis of VILI and on potential preventative and therapeutic strategies.

项目概要/摘要 自从 1952 年丹麦脊髓灰质炎疫情进入临床实践以来，正压机械治疗 通气挽救了无数生命，并实现了全身麻醉下手术的安全实施。 然而，近年来，人们已经清楚机械通气本身可能会通过启动呼吸而损伤肺部。 并传播称为呼吸机诱发性肺损伤（VILI）的炎症过程。 最初主要认为是危重症患者急性呼吸窘迫的加重因素 综合征，新证据表明，肺部未受伤且接受通气的受试者也可能发生这种情况 由于其他原因，例如在接受全身麻醉时。 这项研究的长期目标是 剖析 VILI 的机制并确定改善它的策略。拟议的研究与此相符。 目标是因为他们通过解决总体问题来研究 IL-33/ST2 信号通路的新作用 假设 IL-33 通过影响 NF-κB 介导而成为 VILI 的上游致病效应子 该炎症假说将通过三个紧密结合的具体目标进行测试，目标 1 将建立以下目标。 IL-33 在 VILI 中的作用，证明其表达随潮气量增加，与潮气量平行 已建立的 VILI 细胞因子和 NF-κB 的反应，而 IL-33 缺失会减弱 Aim 2 的这种反应。 通过探索用 IL-33 诱饵受体清除 IL-33 的功效作为中断方法，实现目标 1 IL-33/ST2/NF-κB 信号传导和减少 VILI 中的炎症这一目标将利用一种新型生物制剂。 对 IL-33（“IL-33 陷阱”）具有高亲和力，初步数据表明 IL-33 可能具有治疗潜力。 trap 将与更传统的抗 ST2 受体阻断抗体方法进行比较。 来自目标 1 和 2，因为它将决定机械释放触发 NF-κB 的激活多长时间 通气停止后，像 IL-33 这样的敏感细胞因子仍然存在，从而使肺部容易受到其他细胞因子的影响。 侮辱，以及术后期间可能发生的侮辱，这是贯穿这三者的一个显着特征。 该项目的目标是应用基于正电子发射的独特分子成像方法 NF-κB 转录活性断层扫描 (PET)，以测量 IL-33/ST2 信号传导对下游的影响 细胞因子在体内、非侵入性、重复性且具有高空间分辨率的表达。 临床相关小鼠通气模型、新型 VILI 效应器（IL-33，目标 1）、治疗性药物的组合 生物学（IL-33 陷阱，目标 2）和转化视角（目标 3）将使所提出的实验变得独特 有望提供有关 VILI 发病机制以及潜在预防和预防措施的基本新知识 治疗策略。